Macrophage cytokines: involvement in immunity and infectious diseases

Abstract

The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting "classically activated," to anti-inflammatory or "alternatively activated" macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.

Keywords: Leishmania; Mycobacterium ulcerans; anti-inflammatory; cytokine; exocytosis; macrophage; proinflammatory; trafficking.

Figure 1

Monocytes can become phenotypically distinct macrophages. Upon encountering different stimuli, monocytes turn into highly microbicidal (M1), or into immunosuppressive macrophages (M2). Stimuli can range from microbial substances to biochemical signals provided by the microenvironment of a given tissue. Many of the cytokines that bias macrophage phenotype are provided by surrounding lymphocytes or other non-immune cells. Macrophage subtypes release a vastly different array of cytokines and chemokines that can either promote inflammation and sometimes tissue destruction, or wound healing and tissue repair. M1 macrophages are known to be tumor suppressive whereas M2 macrophages generally promote tumorigenesis. It is important to note that macrophage bias is a spectrum and is reversible. IC, immune complexes; ApC, apoptotic cells; Gluc, glucocorticoids.

Figure 2

Modulation of macrophage cytokine secretion by Mycobacterium ulcerans bacteria and Leishmania promastigotes. Disruption of cytokine release has evolved as an effective means by which several pathogens contravene the immune response. (A) M. ulcerans employs mycolactone to sabotage the immune response by inhibiting the secretion of more than 17 cytokines, chemokines, and inflammatory mediators. TNF, as well as other cytokines and chemokines, undergo post-translational modifications in the ER and Golgi prior to being shepherded outside of the macrophage. Mycolactone hampers delivery of TNF into the ER. As a consequence, immature protein that accumulates in the cytoplasm is eventually degraded by the proteasome. (B) Unlike M. ulcerans, Leishmania promastigotes trigger the release of TNF and IL-6 from infected macrophages via GP63-mediated degradation of Syt XI (a negative regulator of cytokine release). In vivo, GP63 also facilitates the infiltration of inflammatory monocytes and neutrophils to the infection site. Both of these phagocytes are infection targets for Leishmania and aid in establishing infection. These findings can be explained by the fact that TNF and IL-6 mediate phagocyte infiltration by upregulating the expression of adhesion molecules and chemokines. Arrows indicate multiple steps and drawings are not to scale.