The immune system plays an important role in the pathophysiology of many acute and chronic bone disorders, but the specific inflammatory networks that regulate individual bone disorders remain to be elucidated. Here, we characterized the osteoimmunological underpinnings of osteolytic bone disease in Pstpip2 cmo mice. These mice carry a homozygous L98P missense mutation in the Pombe Cdc15 homology family phosphatase PSTPIP2 that is responsible for the development of a persistent autoinflammatory disease resembling chronic recurrent multifocal osteomyelitis in humans. We found that improper regulation of IL-1β production resulted in secondary induction of inflammatory cytokines, inflammatory cell infiltration in the bone, and unremitting bone inflammation. Aberrant Il1β expression precedes the development of osteolytic damage in young Pstpip2 cmo mice, and genetic deletion of Il1r and Il1β, but not Il1α, rescued osteolytic bone disease in mutant mice. Intriguingly, caspase-1 and nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 activation in the inflammasome complex were dispensable for Pstpip2 cmo -mediated bone disease. Thus, our findings establish a critical role for inflammasome-independent production of IL-1β in osteolytic bone disease and identify PSTPIP2 as a negative regulator of caspase-1-autonomous IL-1β production.osteoimmunology | interleukin-1 | autoinflammation

Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases.

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Sulfatide from the outer surface of Mycobacterium tuberculosis blocked priming in cultured human monocytes. Monocytes were primed in vitro with either lipopolysaccharide (LPS) or interferon-gamma. Primed monocytes released increased amounts of superoxide anion (O2-) when stimulated with formyl-methionyl-leucyl-phenylalanine or with phorbol myristate acetate. Primed monocytes also showed increased phagocytosis of sheep erythrocytes and increased release of interleukin 1. When primed monocytes were treated with 10 micrograms/ml of sulfatide, these enhanced functions, characteristic of primed monocytes, returned to levels found in unprimed monocytes. (With respect to these functions and others, monocytes or macrophages primed in vitro by exposure to LPS or interferon-gamma resemble macrophages activated in vivo by infection. In vivo, activated macrophages provide non-specific resistance to infection). Inhibition of priming by sulfatide could be detected within 10 min, but maximum effect of sulfatide required 3 to 5 hr. Sulfatide had no effect on O2- release, if it was added after the cells had been stimulated by PMA, suggesting that sulfatide did not inhibit enzymes involved in formation of O2-, but rather that sulfatide inhibited priming. Increasing the amounts of LPS or interferon-gamma did not counteract the effects of sulfatide. Sulfatide did cause monocytes to release some prostaglandin E2 (less than 1 nM), but the amount was not sufficient to inhibit monocyte functions. The effect of sulfatide was not blocked by indomethacin. Other sulfated compounds and other products of mycobacteria did not produce the sulfatide effect. We conclude that M. tuberculosis has on its outer surface a chemical that directly interferes with monocyte priming. In vivo, M. tuberculosis might use sulfatide to block macrophage activation and thereby resist being killed by macrophages.

We examined the interaction between IFN-gamma, LPS, and glucocorticoids on release of oxygen radicals by human monocytes cultured in vitro. After 48 h culture, monocytes released low amounts of superoxide anion (O2-) when stimulated by PMA or FMLP. Monocytes incubated with either IFN-gamma or LPS became "primed" and released greater amounts of O2- in response to stimuli. Monocytes incubated with hydrocortisone, methylprednisolone, dexamethasone, or prednisolone alone showed decreased release of O2-. Prednisone and progesterone, which are not active glucocorticoids, had no effect. When glucocorticoids were co-incubated with IFN-gamma or LPS, the effect of hydrocortisone and other active steroids was blocked, and the monocytes released high O2-. However, when monocytes were preincubated with hydrocortisone for 24 h before addition of IFN-gamma or LPS, priming for enhanced O2- production by LPS was partially inhibited whereas there was no effect on IFN-gamma priming. We suggest that IFN-gamma and LPS can block the anti-inflammatory effects of glucocorticoids, contributing to increased inflammation at tissue sites; however, the mechanism of this effect may differ for the two macrophage activators. To investigate the mechanisms of priming by IFN-gamma and LPS, we examined the effects of these agents and of hydrocortisone on secretion of IL-1 and TNF-alpha. Both IL-1 and TNF-alpha primed monocytes for enhanced release of O2- in response to PMA. LPS caused monocytes to secrete both IL-1 beta and TNF-alpha. LPS-induced secretion of TNF-alpha and IL-1 beta was completely blocked by hydrocortisone, but the priming effect of LPS on O2- release was only partly blocked. IFN-gamma did not cause monocytes to secrete IL-1 beta or TNF-alpha, under our culture conditions (mononuclear cells cultured in Teflon in endotoxin-free modified Earle's salt solution without serum). Therefore, priming by LPS and IFN-gamma, and the inhibition of priming by glucocorticoids involve mechanisms that extend beyond regulation of secretion of IL-1 and TNF-alpha.

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