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. 2016 Apr 1;149(1):1–12. doi: 10.1111/imm.12605

Figure 3.

Figure 3

Carbon monoxide (CO) impairs the endosome‐to‐lysosome pathway to soluble antigens in myeloid cells. (a) After the extracellular antigen is captured, it fuses with Rab5+ early endosomes. After that, these vesicles can fuse with proteasome/MHC‐I/TAP‐containing endosomes, which drive cross‐presentation. In parallel, antigen‐containing Rab5+ vesicles can fuse with Rab7+ endosomes to form late endosomes and then, sequentially, they can fuse with lysosomes (Lamp1+). These lysosomes harbour a full repertoire of MHC molecules that receive and present the small peptides obtained after the antigen is processed by lysosomal proteases. Once haem oxygenase 1 (HO‐1) is over‐expressed and CO is produced, there is an interference in the fusion between antigen‐containing late endosomes and lysosomes so compromising the correct antigen processing and antigen presentation to T cells. No effect of CO over cross‐presentation has been observed. (b) (i) Under local presence of pathogen‐associated molecular pattern (PAMPs); either by soluble molecules or presence of pathogens, dendritic cells (DCs) become activated. After binding the Toll like receptor 4/ myeloid differentiation factor 2 (TLR4/MD2) complex, LPS induces DC maturation by up‐regulation of co‐stimulatory molecules and secretion of cytokines. In addition, PAMPs cause local tissue damage and release of self‐ and non‐self‐antigens. (ii) Resident DCs capture soluble antigens presenting them to local T cells (something also observed in autoimmunity and graft rejection). Antigen‐containing mature DCs can travel to secondary lymphoid organs and activate antigen‐specific naive T cells. (iii) After PAMPs exposure [or treatment with cobalt protoporphyrin IX (CoPP), for example], DCs over‐express HO‐1, degrade haem‐group and produce CO. This process will modulate the immunogenicity of DCs recovering their initial homeostasis. (iv) CO‐producing mature DCs will lose their capacity to process antigens through the endosome‐to‐lysosome pathway. In addition, DCs reduce their secretion of cytokines. (v) Finally, mature DC‐dependent innate and adaptive immune inflammation is suppressed. Tissue homeostasis is recovered and pathologies caused by PAMPs and either foreign or self‐antigens are restricted.