Abstract

 

   Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Initiation and progression of inflammation involves a complex cellular network, the predominant innate immune cell in inflammation is the monocyte-macrophage.The behavior of this cell type within the inflammation is heterogeneous and depends on the recruitment of diverse monocyte subsets.Recent efforts to elucidate the local tissue microenvironment offers polarization and activation signals which impact on macrophage phenotype . In this paper, we review the

literature addressing the tissue factor in modulating macrophage heterogeneity and activation with adipose tissue, central nervous system,aging.

Key words:inflammation,tissue factor,macrophage heterogeneity and activation,

adipose tissue,central nervous system

Introduction

 

Tissue macrophages have a broad role in the maintenance host defence,immunity,

homeostasis, and act through several mechanisms by destroying bacteria,parasites,

viruses and turmor cells,clearing necrotic debris ,apoptotic and senescent cells,processing antigens and presenting digested peptides to adoptive immunity,remodeling and repairing tissue damage(1,2, Jorge Lloberas et al.,2002,to cites or not to cited,not to cited at best). Macrophages undertaken so diverse burdens are tightly connected with their multiple characters.It has been known for decades that cytokines can alter macrophage functional responses(1,3,4 in Robert D.Stout et al.,2005).Distinct functional phenotypes subsequently were reported to be generated by stimulating macrophages with a variety of agents,including IFN-r,IL-4,IL-10,TGFbeta(4,5-9).In addition,macrophages can reversibly and progressively shift their functional phenotype through a multitude of patterns in response to changes in microenvironmental influences( Robert D.Stout et al.,2005).

 

    Macrophages are highly heterogeneous cells(10-12) that are able to respond to

the specialization function of anatomical sites in tissues, primarily reflecting their local metabolic and immune microenvironment(Siamon Gordon et al.,2005).

Such as in central nerve system , macrophages differ in cytoskeletal functions and migration towards specific CNS cell types under a variety of environmental cues

(Elly JF Vereyken et al.,2011).High fat feeding- induced obesity leads to a phenotypic shift of adipose tissue macrophage(ATM) from an M2-polarized state that may protect aidpocytes from inflammation to an M1 proinflammatory state(Carey N.Lumeng et al.,2007, Justin I. Odegaard and Roberto R. Ricardo-Gonzalez et al.,2007)

Aging associated malfunction of macrophages has contributed to a decline in the functional activity of the immune system(Jorge Lloberas et al.,2002, Julie Plowden et al.,2004). These examples indicate that the tissue microenvironment can markedly influence the phenotype of tissue-resident macrophages(13).Macrophages are a key cell component of the inflammatory reactions expressed at various pathological sites. Understanding the pathogenetic role played by polarized functions may pave the way for the identification of novel therapeutic approaches

 

Macrophage activation and heterogeneity in inflammation

(The spectrum of macrophage:macrophage population,Roles of macrophage in inflammation,2007)

 

In response to cellular differentiation ,wide-spread tissue distribution and many endogenous and exogenous stimuli,Macrophages show significant heterogeneity in function(??14,15??)(14, 16). Different stimuli activate macrophages to express distinct patterns of chemokines, surface markers, and metabolic enzymes that ultimately generate the diversity of macrophage function seen in inflammatory and noninflammatory settings. Macrophage activation has been operationally defined across 2 separate activation status:  interferon-r(IFN-r) mediated classically activated (CA/M1),pro-inflammatory,           

macrophages.Alternatively activated (AA/M2), growth promoting,macrophages, induced by the T helper 2(Th2) cytokines interleukin-4 and IL-13 (17,18). These states have largely been defined in vitro, and tissue macrophages are likely activated along a continuum between these states in vivo(19,20,in Carey N.Lumeng et al.,2007).Mosser et al depict the spectrum showing the linear scale of the two macrophage designations.They propose three populations of macrophages based on their fundamental functions.(1) Classically activated macrophages,are vital components of host defence,predispose to cause host-tissue damage,autoimmune diseases.(2) Wound-healing macrophages,promote the production of extracellular matrix contributing to tissue repair and homeostasis,lead to fibrosis,exacerbate allergic responses.(3)Regulatory macrophages,dampen the immune response and limit inflammation,dysregulated action can contribute to the progression of neoplasia(Mosser and Edwards et al.,2008).Subsequently,Gordon et al argue that the definition on “alternative”form of activation is too loose in macrophage study. For searching potential therapeutic targets,it is required to( ##restrict the previous nomenclature,and ##)take into account the complex effects of the IL-4 and IL-13 dependence combined with cell differentiation, interactions,and local tissue microenvironment in modulating the macrophage pattern(Gordon et al et al.,2010).

 

Key role of adipose tissue in the inflammation response

An important initiator of the inflammatory response to obesity is adipose tissue.Adipose tissue is not merely an organ designed to passively store excess calories. Mature adipocytes synthesize and secrete numerous enzymes, growth factors, cytokines,chemokines and hormones that are involved in diverse processes in the body including lipid homeostasis and modulation of inflammatory responses.Adipocytes secreted termed adipocytokines or adipokines(21–23),that are recurrently reported over 50 different adipokines( http://themedicalbiochemistrypage.org/home.html).

   ###Give a general summary of these adipokines in Table 1####

 

     Researchers found adipose tissues are infiltrated with increased numbers of macrophages in obese mice and human vensus lean counterparts,In addition,the content of these macrophages is in line with the level of obesity (25,26,27,28). Recently,Jerrold Olefsky and Christopher Glass contributed a wonderful review to summarize how adipose tissue modulates macrophage to propagate inflammation.<<They told a very interesting possibility that tissue cytokines in blood may “leak ”into the circulaton and impair insulin sensitivity in distal tissues in an endocrine fashion(29–31;Jerrold and Christopher et al.,2010).>>  They also present activated T cells can modify macrophages behavior and contributed to insulin resistance(32).Th1 lymphocytes may participate macrophage migration and activation to raise the classical activated state ((33,34).While T-reg lymphocytes(Tregs) exert a protective effect to inhihit proinflammatory macrophages for a decrease in adipose tissue T-reg content in obesity(35,36).Another paper with leptin-deficient ob/ob mice,they induced TGF-β-dependent CD4+ latency-associated peptide positive Tregs found compromised status in inflammation,and decreased CD11b+F4/80+ macrophages and TNF-α in adipose tissue (Yaron Ilan and Ruth Maron et al.,2010).Although this furtherly confirms the role of Treg cells contributed to modulate macrophage activaity directly,as well as through cytokines,the molecular mechanisms underlying their contact-dependent interactions are poorly defined still.

 

Organize below in a new detailed table.(cited from websites:) Table of Adipose Tissue Hormones and Cytokines

Adipose tissue produces and releases a vast array of protein signals including (growth factors, cytokines, chemokines, acute phase proteins, complement-like factors, and adhesion molecules,shape this table to new one ). The Table below describes several of the adipocyte proteins in more detail with leptin, adiponectin, and resistin discussed in greater detail in the following sections. The proteins of the various signaling processes are listed below.

 

Factor	Principal Source	Major Action
adiponectin also called adipocyte complement factor 1q-related protein (ACRP30), and adipoQ	adipocytes	see below
adipsin (also called complement factor D)	adipocytes, liver, monocytes, macrophages	rate limiting enzyme in complement activation
apelin	adipocytes, vascular stromal cells, heart	levels increase with increased insulin, exerts positive hemodynamic effects, may regulate insulin resistance by facilitating expression of BAT uncoupling proteins (e.g. UCP1, thermogenein)
chemerin	adipocytes, liver	modulates expression of adipocyte genes involved in glucose and lipid homeostasis such as GLUT4 and fatty acid synthase (FAS); potent anti-inflammatory effects on macrophages expressing the chemerin receptor (chemokine-like receptor-1, CMKLR1)
C-reactive protein (CRP)	hepatocytes, adipocytes	is a member of the pentraxin family of calcium-dependent ligand binding proteins; assists complement interaction with foreign and damaged cells; enhances phagocytosis by macrophages; levels of expression regulated by circulating IL-6; modulates endothelial cell functions by inducing expression of various cell adhesion molecules, e.g. ICAM-1, VCAM-1, and selectins; induces MCP-1 expression in endothelium; attenuates NO production by downregulating NOS expression; increase expression and activity of PAI-1
IL-6	adipocytes, hepatocytes, activated Th2 cells, and antigen-presenting cells (APCs)	acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1 and TNF on T cells
leptin	predominantly adipocytes, mammary gland, intestine, muscle, placenta	see below
monocyte chemotactic protein-1 (MCP-1)	leukocytes, adipocytes	is a chemokine defined as CCL2 (C-C motif, ligand 2); recruits monocytes, T cells, and dendritic cells to sites of infection and tissue injury
omentin	visceral stromal vascular cells of omental adipose tissue	the omentum is one of the peritoneal folds that connects the stomach to other abdominal tissues, enhances insulin-stimulated glucose transport, levels in the blood inversely correlated with obesity and insulin resistance
plasminogen-activator inhibitor-1 (PAI-1)	adipocytes, monocytes, placenta, platelets, endometrium	see the Blood Coagulation page for more details
resistin	adipocytes, spleen, monocytes, macrophages, lung, kidney, bone marrow, placenta	see below
TNFα	primarily activated macrophages, adipocytes	induces expression of other autocrine growth factors, increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation
vaspin	visceral and subcutaneous adipose tissue	is a serine protease inhibitor, levels decrease with worsening diabetes, increase with obesity and impaired insulin sensitivity
visfatin; also called pre-B cell-enhancing factor (PBEF); reported to be the extracellular version of the enzyme nicotinamide phosphoribosyltransferase (Nampt or eNampt), however, the original paper claiming this has been retracted	visceral white adipose tissue	conflicting results relative to insulin receptor binding but blocking insulin receptor signaling interferes with effects of eNampt; changes in eNampt activity occur during fasting and positively regulate the activity of the NAD+-dependent deacetylase SIRT1 leading to alterations in gene expression

 

Central nervous system

 

It is well-accepted that monocytes can replenish tissue-macrophage

numbers,especially during inflammation. However, the origin of the cells involved in this process is unclear,because it’s very complicated to distinguish the relative importance between local expansion and recruitment of microglia progenitors from the bloodstream. Although Monocytes can enter the CNS to populate macrophages (37,38,Siamon Gordon et al.,2005).There are evidences suggest that maintenance and local expansion of

microglia are solely dependent on the self-renewal of CNS resident cells( 19: Ajmi B and Bennett JL et al.,2007).Macrophages are important mediators in bridging innate and acquired immunity during neuroinflammation.Which can shape their phenotype and physiology to adapt to the local tissue microenvironment[39,40](13,14,Lument et al.,2007).In tissues, the microenvironment of the macrophages is thought to determine the phenotype [41].In vitro, cytokines and other stimuli induce these activation phenotypes. Recently,Christine D Dijkstra and colleagues published a research article to describe the characteristics of these phenotypically different macrophages in the context of the CNS. Their experiments present classically activated(CA) and alternatively activated(AA) macrophages behave differently incubated with the conditional media of CNS cells.

(show in table 2)###in addition,give a description shortly###

 

Table 2:based on Elly JF Vereyken et al,.2011 summarize in detail,continue…..

 

Effect of aging on macrophages(human macrophages AND on animal models)

 

Macrophages originate in the bone marrow and migrate to body tissues through blood,and therefore,which generally provide a limited view of tissue macrophages.CD68 positive cells,the markers of macrophage population ,have a dramatic decrease observed in the bone marrow of elderly people(Ogawa et al.,2000). Cell lifespan can be regulated mainly by telomeres and telomerases (Iwama et al., 1998).Telomere length and activity serve as biological regulators of the limited division potential of human cells.While terminal differentiated cells do not express telomerase(Weng, 2001).In order to uncover the functional activities of macrophages,several experiments have been performed to check the capacity of these cells to produce cytokines or chemokines(Beharka et al.,2001; Gon et al., 1996; Roubenoff et al., 1998;O’Mahony et al., 1998; Sadeghi et al., 1999;

Ahluwalia et al., 2001; Mariani et al., 2002).Unfortunately,these reports are very contradictory mutually.However,some other reports suggest a decrease expression of scavenger receptor and apolipoprotein E, low respiratory burst of monocytes and susceptibility to stress-induced apoptosis during aging (Alvarez and Santa Maria, 1996;Monti et al., 2000).

Experiments on animal models show impaired TNF-a production,

Norepinephrine-induced chemotaxis and transcription of IAb gene (Corsini et al., 1999; Ortega et al., 2000).Aged macrophages treated with IFN-g produce lower MHC class II gene IA Complex,and intracellular IAb protein and mRNA(Herrero et al., 2001).Whereas treated with LPS produce more TNF-a and prostaglandin I than those from young animals(Tang et al., 2000)These results suggest that aged macrophages don’t work normally as young,further studies to clearify the phenotypic alteration and disclose the key molecular mechanisms of macrophage in aging state are very appreciated.

 

Concluding remarks

Macrophages,Inflammation ,CAD.pdf

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