The knowledge about the contribution of the innate immune system to health and disease is expanding. However, to obtain reliable results, it is critical to select appropriate mouse models for in vivo studies. Data on genetic and phenotypic changes associated with different mouse strains can assist in this task. Such data can also facilitate our understanding of how specific polymorphisms and genetic alterations affect gene function, phenotypes, and disease outcomes. Extensive information is available on genetic changes in all major mouse strains. However, comparatively little is known about their impact on immune response and in particular on innate immunity. Here, we analyzed a mouse model of chronic multifocal osteomyelitis (CMO), an autoinflammatory disease driven exclusively by the innate immune system, which is caused by an inactivating mutation in the Pstpip2 gene. We investigated how the genetic background of BALB/c, C57BL/6J, and C57BL/6NCrl strains alters the molecular mechanisms controlling disease progression. While all mice developed the disease, symptoms were significantly milder in BALB/c and partially also in C57BL/6J when compared to C57BL/6NCrl. Disease severity correlated with the number of infiltrating neutrophils and monocytes and with the production of chemokines attracting these cells to the site of inflammation. It also correlated with increased expression of genes associated with autoinflammation, rheumatoid arthritis, neutrophil activation, and degranulation, resulting in altered neutrophil activation in vivo. Together, our data demonstrate striking effects of genetic background on multiple parameters of neutrophil function and activity influencing the onset and course of the CMO disease.

Autoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo . In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1.
To address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers.
Our data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues.
We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.

Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory bone disease for which a lack of bacterial involvement is a key diagnostic feature to distinguish it from other symptomatically related diseases. However, the growing evidence suggesting an involvement of the host-associated microbiota in rheumatic disorders together with the now wide accessibility of modern culture-independent methods warrant a closer examination of CRMO.
In this study, we show through bacterial 16S rRNA gene profiling that numerous features of the oral- and fecal microbial communities differentiate children with and without CRMO.
Notably, communities in diseased children are characterized by a lack of potential probiotic bacteria in the fecal community and an overabundance of known pathobionts in the oral microbial communities. Of special interest is the HACEK group, a set of commonly known oral pathogens that are implicated in the development of several acute and chronic diseases such as osteitis and rheumatoid arthritis. Furthermore, we observe that gut bacterial communities in the diseased children appear to reflect an altered host physiology more strongly than the oral community, which could suggest an oral disease origin followed by propagation and/or responses beyond the oral cavity.
Bacterial communities, in particular the oral microbiota, may serve as an indicator of underlying susceptibility to CRMO, or play a yet undefined role in its development.

A case of chronic multifocal osteomyelitis was described in terms of its clinical manifestations, serological and imaging examinations, diagnostic criteria, treatment options, and follow-up evaluation after discharge. The pathogenesis, diagnosis, differential diagnosis and treatment of chronic multifocal osteomyelitis were reviewed, and the characteristics of autoinflammatory osteopathy were reviewed. The patient with onset from youth had developed severe skin lesions, progressive arthralgia and rachialgia. The clinical manifestation and the auxiliary examination of the patient accorded with the diagnosis of chronic multifocal osteomyelitis. After poor anti-inflammatory and analgesic effects, the switch to tumor necrosis factor alpha (TNF-α) inhibitor resulted in pain relief, normalization of inflammation indexes, and significant improvement in rash and imaging examination. Chronic recurrent multifocal osteomyelitis was a kind of autoinflammatory bone disease of multiple genes in disease with low incidence, unknown mechanism and unified diagnostic criteria. It was also known as chronic nonbacterial osteomyelitis, which was a rare, noninfectious inflammatory disorder that caused multifocallytic bone lesions characterized by periodic exacerbations and remissions. The exact pathophysiology or mechanism of the sterile bone inflammation was poorly understood, although chronic nonbacterial osteomyelitis was probably an osteoclast-mediated disease. In addition, an imbalance between pro- and anti-inflammatory cytokines was suspected to play a role. The available data so far pointed to the interplay among genetics, environmental, and immunologic factors as the causes of chronic nonbacterial osteomyelitis. Infectious etiology did not seem to play a crucial role in the pathogenesis of chronic nonbacterial osteomyelitis. It was often confused with metabolic bone disease, infection, tumor and other diseases. Its clinical manifestations were bone pain, fever, rash, fracture and so on. Laboratory examination showed significant increase in inflammatory markers. Radiographic examination revealed osteolytic or sclerosing changes. Magnetic resonance imaging was very useful for identifying bone lesions and tissue edema and was more accurate than bone emission computed tomography (ECT). Most of the patients begin to use non-steroidal anti-inflammatory drugs (NSAIDs) for treatment, but they are prone to relapse and new lesions appear. Other treatment options can be selected, including glucocorticoids, TNF-α inhibitors, bisphosphonates, methotrexate and other disease-modifying anti-rheumatic drugs (DMARDs). Early diagnosis and treatment can prevent and reduce complications and improve prognosis.