Orchitis

BackgroundApproximately 8-9% of the world's population is affected by autoimmune diseases, and yet the mechanism of autoimmunity trigger is largely understudied. Two unique cell death modalities, ferroptosis and pyroptosis, provide a new perspective on the mechanisms leading to autoimmune diseases, and development of new treatment strategies.MethodsUsing scRNA-seq datasets, the aberrant trend of ferroptosis and pyroptosis-related genes were analyzed in several representative autoimmune diseases (psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn's disease, and experimental autoimmune orchitis). Cell line models were also assessed using bulk RNA-seq and qPCR.ResultsA substantial difference was observed between normal and autoimmune disease samples involving ferroptosis and pyroptosis. In the present study, ferroptosis and pyroptosis showed an imbalance in different keratinocyte lineages of psoriatic skinin addition to a unique pyroptosis-sensitive keratinocyte subset in atopic dermatitis (AD) skin. The results also revealed that pyroptosis and ferroptosis are involved in epidermal melanocyte destruction in vitiligo. Aberrant ferroptosis has been detected in multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn's disease, and autoimmune orchitis. Cell line models adopted in the study also identified pro-inflammatory factors that can drive changes in ferroptosis and pyroptosis.ConclusionThese results provide a unique perspective on the involvement of ferroptosis and pyroptosis in the pathological process of autoimmune diseases at the scRNA-seq level. IFN-γ is a critical inducer of pyroptosis sensitivity, and has been identified in two cell line models.

Brucellosis is a common zoonotic disease that is widely spread worldwide and poses a major threat to human health. Clinically, it often presents with non-specific symptoms such as fever, excessive sweating, malaise, myalgia, arthralgia, loss of appetite, weight loss, and enlarged liver, spleen and lymph nodes. The disease has a long and recurrent course, often accumulating in multiple systems and organs. Of these, osteoarticular involvement is the most common complication, with a prevalence of approximately 2-77%, usually manifesting as spondylitis, sacroiliac arthritis and peripheral arthritis. Hepatosplenomegaly is seen in about 50% of patients with brucellosis, and gastrointestinal disturbances such as abdominal pain, nausea, and vomiting are common. Although respiratory involvement is less common, pneumonia, pleurisy, pleural effusion, and pulmonary nodules have been reported. Besides, approximately 2-20% of cases involve infections of the male genitourinary system, mainly manifesting as unilateral epididymal-orchitis and orchitis. The most serious complication facing brucellosis is cardiovascular involvement, and although the overall mortality rate of brucellosis is about 1% and the incidence of brucellosis endocarditis is less than 2%, more than 80% of deaths are associated with endocarditis. Furthermore, brucellosis is complicated by hematologic disease, with anemia occurring in approximately 20-53% of children during the acute phase. In addition, the neurological incidence of brucellosis is about 0.5-25%, mainly manifested as meningitis. In this study, we review the multisystem complications of brucellosis with the aim of improving early diagnosis, timely treatment and prevention of long-term complications.

BackgroundVaricocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system.ResultsThe testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB).ConclusionsThe testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

Bacterial orchitis is a major cause of male infertility, yet effective therapies remain limited. Although the itaconate derivative 4-octyl itaconate (4-OI) possesses potent anti-inflammatory properties, its role in testicular inflammation is unclear. Here, we investigated the protective effects and mechanisms of 4-OI in lipopolysaccharide (LPS)-induced inflammatory injury using Sertoli cells and a mouse model of acute orchitis. LPS activated NF-κB/NLRP3 signaling and induced excessive autophagy in Sertoli cells, resulting in oxidative stress, apoptosis, disruption of tight junctions, and functional impairment. 4-OI markedly suppressed NF-κB phosphorylation and NLRP3 activation, reduced mitochondrial oxidative stress, and improved cell viability. Mechanistically, 4-OI inhibited excessive autophagy by downregulating UNC-51-like kinase 1 (ULK1) and autophagy-related proteins, thereby limiting autophagic flux. Consequently, Sertoli cell functional markers, tight junction integrity, and mitochondrial homeostasis were restored. In vivo, 4-OI alleviated testicular histopathological damage, reduced germ cell apoptosis, improved sperm quality, preserved blood-testis barrier integrity, and enhanced spermatogenic activity. Collectively, these findings identify ULK1-associated excessive autophagy as a key mechanism of inflammatory testicular injury and demonstrate that 4-OI protects against orchitis-induced reproductive dysfunction, highlighting its therapeutic potential for inflammation-associated male infertility.