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Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found myeloid specific deletion of mitochondrial Complex I protein Ndufs4 (mKO) reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to lipopolysacharride. Moreover, mKO mice showed increased mortality, poor scar formation and worsened cardiac function 30 days post-MI. We observed a greater inflammatory response in mKO on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to reparative phase during day 3-7 post-MI. Efferocytosis is markedly impaired in mKO macrophages leading to lower expression of anti-inflammatory cytokine and tissue repair factors, which suppressed the proliferation/activation of myofibroblasts in the infarct area. Mitochondria-targeted ROS scavenging rescued these impairments and improved myofibroblast function in vivo and reduced post-MI mortality in mKO mice. Together these results reveal a novel role of mitochondria in inflammation resolution and tissue repair via modulating efferocytosis and crosstalk with fibroblasts. The findings are significant for post-MI recovery as well as for other inflammatory conditions.

While a causal relationship between pain-related fear and spinal movement avoidance in patients with chronic low back pain (CLBP) has frequently been postulated, evidence supporting this relationship is limited. This study aimed to test if decreases in pain-related fear or catastrophizing were associated with improvements in spinal biomechanics, accounting for possible changes in movement-evoked pain.

"Non-inflammatory" pain, pain that is not associated with measures of inflammation, is common in patients with inflammatory arthritis including rheumatoid arthritis (RA). One important cause of non-inflammatory pain is concomitant fibromyalgia. Systematic review has shown that fibromyalgia is common in inflammatory arthritis including RA affecting 1 in 5 patients and is associated with higher disease activity scores due to inflated tender joint count and patient global assessment. Consequently, many patients with RA and concomitant fibromyalgia may fail to reach treatment target and switch to alternate disease modifying drugs frequently. European Alliance of Association for Rheumatology has highlighted that concomitant fibromyalgia is an important consideration in assessing difficult-to-treat RA. The incidence and prevalence of fibromyalgia are higher in RA than the general population raising the possibility that fibromyalgia may be "secondary "to RA rather than a concomitant disease. The precise mechanisms whereby patients with RA develop fibromyalgia are unknown. In this review, we discussed fibromyalgia in RA, its clinical impact and epidemiology as well as data suggesting fibromyalgia might be "secondary". Lastly, we reviewed potential pathogenic mechanisms which included inflammatory cytokines sensitizing nociceptive neurones, temporal summation, also known as windup, from chronic pain and impaired coping from poor quality sleep and mental well-being. Deciphering the exact mechanisms may lead to treatment strategies that prevent development of secondary fibromyalgia and will address a common factor associated with difficult to treat RA.

Peripheral sensitization contributes to pathological pain. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C-nociceptors (TRPV1+), glial cell line-derived neurotrophic factor (GDNF) sensitizes non-peptidergic C-neurons (IB4+). Sigma-1 receptor (σ1R) is a Ca -sensing chaperone known to modulate analgesia induced by opioid drugs. This receptor binds both to TRPV1 and the μ-opioid receptor (MOPr), although the functional repercussions of these physical interactions in peripheral sensitization are unknown.

Adolescents with recurrent pain miss out from school more often than pain-free peers. Research has so far used cross-sectional designs, focusing on non-specific absenteeism in clinical samples. Hence, it is unknown whether estimates of absenteeism are specifically linked to the pain itself or reflects the characteristics of clinical samples. This study aimed to prospectively explore pain-related school absenteeism in a non-clinical sample, its variance and potential risk factors.

Modern antiretroviral therapy (ART) has increased longevity of people with HIV (PWH) and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical aging due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of antiretroviral therapy (ART) and biological aging. Here we present results of comprehensive assessments over 12 years of 402 PWH in the CNS HIV ART Effects Research (CHARTER) program, who at follow-up were composed of younger (<60 years) and older (≥60 years) subgroups. Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical aging. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression, and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive aging due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among PWH than in the general population. Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in PWH may be warranted in their care.

TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ-motif containing GTPase activating protein 1 (IQGAP1) is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQGAP1 bind to each other and are highly colocalised in sensory DRG neurons in mice. The expression of IQGAP1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of DRG neurons catalysed by the small GTPase Cdc42 associated with IQGAP1, leading to functional sensitization of the channel. Activation of PKA is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQGAP1. Concordantly, deletion of IQGAP1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQGAP1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels.