Macrophage Function Disorders

Abstract

Macrophages are sentinel cells of the innate immune response. Macrophages recognise pathogen‐associated molecular patterns (e.g. microbial products) and endogenous ligands (e.g. apoptotic cells) through a broad and adaptable range of pattern‐recognition receptors. The consequence of this recognition is generally effective clearance via phagocytosis; however, when this is not effective, macrophages may become inappropriately activated and initiate an inappropriate inflammatory response. Because macrophages are extremely variable in phenotype and function and share a common ancestry with monocytes and dendritic cells, there are very few genes that are expressed exclusively in macrophages. Consequently, macrophage‐specific immunodeficiencies are rare. There are, however, a number of genetic immunodeficiencies that affect macrophage function. In addition, as macrophages are exquisitely attuned to their microenvironment, their function appears to be adversely affected by and contributes to chronic inflammatory conditions such as cancer, atherosclerosis and obesity. Thus, genetic deficiencies, in addition to microenvironmental dysregulation, can contribute to macrophage function disorders.

Key Concepts:

  • Macrophages functions include sensing of modified host proteins, microbes and microbial components. Macrophages respond to these ligands primarily through phagocytic and inflammatory receptors.

  • Macrophage function is exquisitely attuned to the microenvironment and when chronic inflammatory conditions alter the microenvironment, macrophage function can become impaired.

  • Primary immunodeficiencies have been identified that impair macrophage phagocytosis and inflammatory responses and leave the patient susceptible to infectious disease and other chronic conditions.

  • Macrophages are able to sense a wide and diverse variety of endogenous and exogenous ligands, including modified host proteins, microbes, and microbial components.

  • Chronic inflammatory conditions such as cancer and atherosclerosis alter the microenvironment, which can impair the ability of macrophages to maintain homeostasis.

Keywords: cellular immunity; chronic inflammation; inflammation; macrophages; monocytes; pattern‐recognition receptors; phagocytosis

Figure 1.

Inflammatory PRRs expressed by macrophages. The surface expressed TLRs (TLR1,2,4,5,6,10,11 and 12), recognised conserved bacterial and fungal components including both bacterial cell wall components (LPS, LTA and lipoproteins), flagellin components and some host ligands. Most of these surface expressed TLRs require coreceptors (e.g. CD14 and MD2, CD36) for efficient binding and signalling (not pictured). These receptors use the common adaptor protein MyD88 and some (TLR2 and TLR4) may also signal from the endosome using alternative adaptor proteins to induce an interferon response. The endosomal‐restricted receptors, TLR3, 7, 8 and 9 recognise bacterial and viral nucleic acids and induce NF‐κB and in the case of TLR3 an antiviral response via the induction of interferon. The cytosolic RIG‐1 or MDA5 sense viral nucleic acids and induce interferon responses, whereas the inflammasome recognises bacterial cell wall components (e.g. peptidoglycan) and other ligands to induce formation of the inflammasome and production of IL‐1β.

close

References

Al‐Herz W , Bousfiha A , Casanova J‐L (2011) Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Frontiers in Immunology 2, 54.

Atkins GJ and Findlay DM (2012) Osteocyte regulation of bone mineral: a little give and take. Osteoporosis International 23(8): 2067–2079.

Badolato R (2004) Leukocyte circulation: one‐way or round‐trip? Lessons from primary immunodeficiency patients. Journal of Leukocyte Biology 76(1): 1–6.

Bae YS , Lee JH , Choi SH et al. (2009) Macrophages generate reactive oxygen species in response to minimally oxidized low‐density lipoprotein: toll‐like receptor 4‐ and spleen tyrosine kinase‐dependent activation of NADPH oxidase 2. Circulation Research 104(2): 210–218, p. 221 following 218.

Barbalat R , Ewald SE , Mouchess ML and Barton GM (2011) Nucleic acid recognition by the innate immune system. Annual Review of Immunology 29, 185–214.

Biswas SK and Mantovani A (2012) Orchestration of metabolism by macrophages. Cell Metabolism 15(4): 432–437.

Blander JM and Medzhitov R (2004) Regulation of phagosome maturation by signals from toll‐like receptors. Science 304(5673): 1014–1018.

Champion JA , Katare YK and Mitragotri S (2007) Particle shape: a new design parameter for micro‐ and nanoscale drug delivery carriers. Journal of Controlled Release 121(1–2): 3–9.

Champion JA , Walker A and Mitragotri S (2008) Role of particle size in phagocytosis of polymeric microspheres. Pharmaceutical Research 25(8): 1815–1821.

Coussens LM and Pollard JW (2011) Leukocytes in mammary development and cancer. Cold Spring Harbor Perspectives in Biology 3(3): pii: a003285. DOI:10.1101/cshperspect.a003285.

Coussens LM , Zitvogel L and Palucka AK (2013) Neutralizing tumor‐promoting chronic inflammation: a magic bullet? Science 339(6117): 286–291.

Derecki NC , Quinnies KM and Kipnis J (2011) Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice. Brain, Behavior, and Immunity 25(3): 379–385.

Ferwerda B , Ferwerda G , Plantinga TS et al. (2009) Human dectin‐1 deficiency and mucocutaneous fungal infections. New England Journal of Medicine 361(18): 1760–1767.

Fleming BD and Mosser DM (2011) Regulatory macrophages: setting the threshold for therapy. European Journal of Immunology 41(9): 2498–2502.

Greaves DR and Gordon S (2009) The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. Journal of Lipid Research 50(Suppl): S282–S286.

Hashizume M and Mihara M (2012) Atherogenic effects of TNF‐alpha and IL‐6 via up‐regulation of scavenger receptors. Cytokine 58(3): 424–430.

Hodge S , Hodge G , Scicchitano R , Reynolds PN and Holmes M (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunology and Cell Biology 81(4): 289–296.

Hopkinson‐Woolley J , Hughes D , Gordon S and Martin P (1994) Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. Journal of Cell Science 107(Pt 5): 1159–1167.

Johnson AR , Milner JJ and Makowski L (2012) The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Reviews 249(1): 218–238.

Joyce JA and Pollard JW (2009) Microenvironmental regulation of metastasis. Nature Reviews Cancer 9(4): 239–252.

Kawai T and Akira S (2010) The role of pattern‐recognition receptors in innate immunity: update on toll‐like receptors. Nature Immunology 11(5): 373–384.

Kerrigan AM and Brown GD (2009) C‐type lectins and phagocytosis. Immunobiology 214(7): 562–575.

Kerrigan AM and Brown GD (2011) Syk‐coupled C‐type lectins in immunity. Trends in Immunology 32(4): 151–156.

Koltsova EK , Garcia Z , Chodaczek G (2012) Dynamic T cell‐APC interactions sustain chronic inflammation in atherosclerosis. Journal of Clinical Investigation 122(9): 3114–3126.

Korzenik JR and Dieckgraefe BK (2000) Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease. Digestive Diseases and Sciences 45(6): 1121–1129.

Ma MJ , Wang HB , Li H et al. (2011) Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population. PLoS One 6(8): e24069.

Mahoney KH , Morse SS and Morahan PS (1980) Macrophage functions in beige (Chediak–Higashi syndrome) mice. Cancer Research 40(11): 3934–3939.

Martinez FO , Sica A , Mantovani A and Locati M (2008) Macrophage activation and polarization. Frontiers in Bioscience 13: 453–461.

Mestas J and Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. Journal of Immunology 172(5): 2731–2738.

Metschnikoff E (1884) Untersuchungen über die intracelluläre Verdauung bei wirbellosen Thieren. (Mit 2 Tafeln). Arbeiten aus dem Zoologischen Institut der Universität Wien, und der Zoologischen Station in Triest. Wien 5: 141–168.

Moilanen P , Korppi M , Hovi L et al. (2009) Successful hematopoietic stem cell transplantation from an unrelated donor in a child with interferon gamma receptor deficiency. Pediatric Infectious Disease Journal 28(7): 658–660.

Mukhopadhyay S , Chen Y , Sankala M et al. (2006) MARCO, an innate activation marker of macrophages, is a class A scavenger receptor for Neisseria meningitidis . European Journal of Immunology 36(4): 940–949.

Mukhopadhyay S , Pluddemann A and Gordon S (2009) Macrophage pattern recognition receptors in immunity, homeostasis and self tolerance. Advances in Experimental Medicine and Biology 653: 1–14.

Nguyen KD , Qiu Y , Cui X et al. (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480(7375): 104–108.

Pace JL and Russell SW (1981) Activation of mouse macrophages for tumor cell killing. I. Quantitative analysis of interactions between lymphokine and lipopolysaccharide. Journal of Immunology 126(5): 1863–1867.

Qian BZ and Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1): 39–51.

Rathinam VA et al. (2012) Regulation of inflammasome signaling. Nature Immunology 13(4): 333–332.

Rennert H , Zeigler‐Johnson CM , Addya K et al. (2005) Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men. Cancer Epidemiology, Biomarkers and Prevention 14(4): 949–957.

Russell DG and Yates RM (2007) Toll‐like receptors and phagosome maturation. Nature Immunology 8(3): 217; author reply 217–218.

Stein M , Keshav S , Harris N and Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. Journal of Experimental Medicine 176(1): 287–292.

Swanson JA and Hoppe AD (2004) The coordination of signaling during Fc receptor‐mediated phagocytosis. Journal of Leukocyte Biology 76(6): 1093–1103.

Swirski FK and Nahrendorf M (2013) Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339(6116): 161–166.

Taylor PR , Martinez‐Pomares L , Stacey M et al. (2005) Macrophage receptors and immune recognition. Annual Review of Immunology 23: 901–944.

von Bernuth H , Picard C , Jin Z et al. (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321(5889): 691–696.

Weisberg SP , McCann D , Desai M (2003) Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation 112(12): 1796–1808.

Whelan FJ , Meehan CJ , Golding GB , McConkey BJ and Bowdish DM (2012) The evolution of the class A scavenger receptors. BMC Evolutionary Biology 12: 227. DOI: 10.1186/1471-2148-12-227.

Xu H , Barnes GT , Yang Q et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity‐related insulin resistance. Journal of Clinical Investigation 112(12): 1821–1830.

Yi H , Guo C , Yu X et al. (2011) Targeting the immunoregulator SRA/CD204 potentiates specific dendritic cell vaccine‐induced T‐cell response and antitumor immunity. Cancer Research 71(21): 6611–6620.

Zhang SY , Boisson‐Dupuis S , Chapgier A et al. (2008) Inborn errors of interferon (IFN)‐mediated immunity in humans: insights into the respective roles of IFN‐alpha/beta, IFN‐gamma, and IFN‐lambda in host defense. Immunological Reviews 226: 29–40.

Further Reading

Dennehy KM , Willment JA , Williams DL and Brown GD (2009) Reciprocal regulation of IL‐23 and IL‐12 following co‐activation of Dectin‐1 and TLR signaling pathways. European Journal of Immunology 39(5): 1379–1386.

Heinsbroek SE , Taylor PR , Rosas M et al. (2006) Expression of functionally different dectin‐1 isoforms by murine macrophages. Journal of Immunology 176(9): 5513–5518.

Ochs HD , Smith CIE and Puck JM (eds) (1999) Primary Immunodeficiency Disease: A Molecular and Genetic Approach. Oxford: University Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lee, Keith M, Yin, Charles, Verschoor, Chris P, and Bowdish, Dawn ME(Sep 2013) Macrophage Function Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002174.pub3]