The Role of Macrophages in the Pathogenesis of ALI/ARDS

Figure 1

The molecular mechanism of SOCS- and IRF-regulated cytokine signaling in macrophages during ALI/ARDS. (a) Normal resident AMs are activated and shift into the M1 phenotype upon certain stimulation during the exudative phase of ALI/ARDS. Proinflammatory cytokines such as IFN-γ, TNF-α, and IL-β are excreted by M1 macrophages into the site of inflammation. The JAK–STAT1 pathway is activated by IFN-γ, and SOCS1 and SOCS3 are induced. SOCS1 and SOCS3 inhibit the signaling pathway by different mechanisms. IRF5 promotes M1 polarization by directly binding to IL-12 and IL-23 promoters. Leukocytes migrate into the cellular airspace by the activation of chemokines such as KC, MIP-2, and IL-8. Monocytes from the circulation are also recruited by chemokines such as MCP-1 and shift into the M1 phenotype. Crosstalk between SOCS3 and IRF5 may exist. (b) Macrophages shift from the M1 phenotype to the M2 phenotype during the later phase of ALI/ARDS. This process is regulated by several factors, including IL-4, IL-10, IL-13, STAT6, and IRF4. IL-4 or IL-13 activates the JAK–STAT6 pathway, and SOCS1 is induced. SOCS1 feedback inhibits the IL-4/IL-13 signaling. IRF4 inhibits IRF5 activation by a competing interaction with the adaptor MyD88. Recruited macrophages play an important role in eliminating apoptotic cells, debris, and pathogens. AMs: alveolar macrophages; IFN-γ: interferon-γ; JAK: Janus kinase; IL: interleukin; STAT: signal transducer and activator of transcription; IRF: interferon regulator factor; SOCS: suppressors of cytokine signaling; KC: keratinocyte-derived chemokine; MIP: macrophage inflammatory protein; MCP: monocyte chemoattractant protein; TNF-α: tumor necrosis factor α; TLR: toll-like receptor; MyD88: myeloid differentiation factor 88.

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