Editors' ChoiceInflammation

An alternative path for pyrin

Sci. Signal.  20 Dec 2016:
Vol. 9, Issue 459, pp. ec299
DOI: 10.1126/scisignal.aam6054

Familial Mediterranean fever (FMF) is a recessive hereditary inflammatory syndrome, which is characterized by recurring pain and periodic fevers. FMF affects an estimated 150,000 people worldwide, with up to one in four individuals carrying FMF alleles in some ethnic groups. The disorder is associated with numerous mutations in MEFV, which encodes pyrin, a protein that binds to the adaptor ASC and the pro form of the enzyme caspase-1 to generate multiprotein complexes called inflammasomes in response to certain infections. In healthy individuals, pyrin-mediated inflammasome assembly—which leads to the caspase 1–dependent processing and secretion of the proinflammatory cytokines interleukin-18 (IL-18) and IL-1β—is a response to enterotoxins from certain bacteria, including the intestinal pathogen Clostridium difficile. Van Gorp et al. found that pyrin-mediated signaling in response to C. difficile infection required functional microtubule assembly in wild-type cells but not those possessing FMF-associated mutations. A C. difficile–secreted toxin, TcdA, induced pyrin-dependent IL-1β secretion by mouse bone marrow–derived macrophages (BMDMs) and peripheral blood mononuclear cells (PBMCs) from healthy human donors. Knowing that pyrin associates with the cytoskeleton, the authors tested the effects of various cytoskeletal inhibitors on TcdA-induced inflammasome activation. The microtubule polymerization inhibitor colchicine, but not its inactive isomer, completely inhibited caspase-1 maturation and IL-1β secretion from BMDMs and PMBCs treated with TcdA. Several structurally unrelated microtubule polymerization inhibitors had the same effect. In contrast, colchicine had no effect on the activation of non-pyrin–containing inflammasomes by anthrax toxin or Salmonella infection, suggesting that the dependence on microtubules is specific to the pyrin inflammasome. In PMBCs from FMF patients with diverse MEFV mutations, colchicine did not inhibit TcdA-induced IL-1β secretion, suggesting that the FMF mutations rendered this immune response independent of microtubule assembly. In cells from patients with CAPS disease and juvenile idiopathic arthritis, immune disorders associated with mutations in genes encoding inflammasome components other than pyrin, colchicine inhibited the response to TcdA similarly to that in healthy donor cells. A known FMF mutation did not affect the binding of ectopically expressed FLAG-tagged pyrin to endogenous tubulin, nor did the mutation affect the dephosphorylation of pyrin in response to TcdA, which is required for pyrin activation. Rather, microtubules appeared to be required in wild-type cells for inflammasome assembly, which was detected by imaging the formation of ASC-containing “specks.” In FMF PMBCs, ASC specks formed in response to TcdA even after treatment with colchicine. These results could help to develop immunological diagnostic markers to distinguish FMF patients from those with other autoinflammatory disorders. Because toxins from some hypervirulent C. difficile strains can affect host microtubules, the authors speculate that the FMF alleles might have persisted in human populations because they remove the requirement for microtubule assembly in the immune response to this infection.

H. Van Gorp, P. H. V. Saavedra, N. M. de Vasconcelos, N. Van Opdenbosch, L. Vande Walle, M. Matusiak, G. Prencipe, A. Insalaco, F. Van Hauwermeiren, D. Demon, D. J. Bogaert, M. Dullaers, E. De Baere, T. Hochepied, J. Dehoorne, K. Y. Vermaelen, F. Haerynck, F. De Benedetti, M. Lamkanfi, Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in pyrin inflammasome activation. Proc. Natl. Acad. Sci. U.S.A. 113, 14384–14389 (2016). [PubMed]

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