Update: Cytokine Dysregulation in Chronic Nonbacterial Osteomyelitis (CNO)

Figure 2

Possible pathophysiological mechanisms in autoinflammatory diseases with emphasis on CNO. Modified from [8, 9]. Endogenous and exogenous danger signals (danger-associated molecular patterns: DAMPs and pathogen-associated molecular patterns: PAMPs) activate the NLRP3 inflammasome that is involved in various autoinflammatory disorders. The exact pathways that result in NLRP3 activation are yet unknown. However, reactive oxygen species (ROS) and lysosomal destabilization seem to be involved. The selected monogenic autoinflammatory syndromes result in an activation of the caspase-1 complex. In PAPA, mutations in PSTPIP1 lead to prolonged binding of PSTPIP1 to pyrin via an SH3 domain [10] and impairment of pyrin function, resulting in constitutive activation of NLRP3, production of IL-1β, and inflammation. IL-1 receptor antagonist (IL-1RA) is a naturally occurring IL-1β antagonist, and mutations in the IL1RA gen lead to DIRA. Based on the finding that Sp1 binding to the IL10 promoter is reduced, and H3S10 phosphorylation is impaired in the same region in monocytes from CNO patients, we concluded that processes upstream of Sp1 activation and H3S10 phosphorylation may be involved. A reduced activity of MAP kinases upstream of Sp1 signalling may be responsible, resulting in reduced Sp1 activation and reduced H3S10 phosphorylation of the IL10 proximal promoter. ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; Casp1: enzymatically active caspase-1; IL-18: interleukin-18; IL-1β: interleukin-1β; NLRP3: NOD-like receptor family, pyrin domain containing 3; pro-Casp1: procaspase-1; ROS: reactive oxygen species; CNO: chronic nonbacterial osteomyelitis; DIRA: deficiency in IL-1 receptor antagonist; PAPA: pyogenic arthritis, pyoderma gangrenosum and acne; PSTPIP1: proline-serine-threonine phosphatase-interacting protein 1.