Cell type specific IL-27p28 (IL-30) deletion uncovers an unexpected pro-inflammatory property of IL-30 in autoimmune inflammation

IL-27 is an IL-12 family cytokine with potent immunoregulatory properties, capable of modulating inflammatory responses, including autoimmunity. While extensive studies have been performed to investigate the major target cells of IL-27 mediating its functions, the source of IL-27 especially during tissue specific autoimmune inflammation has not formally been tested. IL-27p28 subunit, also known as IL-30, was initially discovered as an IL-27-specific subunit, and its expression has thus been used as a surrogate for IL-27. However, there is emerging evidence that IL-27p28 can be secreted without Ebi3, a subunit that forms IL-27 with IL-27p28. Furthermore, IL-27p28 was also reported to act as a negative regulator antagonizing IL-27. In this study, we utilized various cell type specific IL-27p28-deficient mouse models and examined the major source of IL-27p28 in T cell mediated autoimmune neuroinflammation. We found that dendritic cell-derived IL-27p28 is dispensable for the disease development but that IL-27p28 expressed by infiltrating and CNS resident APC subsets, namely, infiltrating monocytes, microglia, and astrocytes, play an essential role in limiting inflammation. Unexpectedly, we observed that cell type specific IL-27p28 deficiency expressing severe disease phenotype is associated with dysregulated IL-27p28 expression in otherwise unaffected APC subsets, suggesting that disproportionate IL-27p28 expressed may increase disease susceptibility. Indeed, systemic recombinant IL-30 administration also induced severe disease. Taken together, our results uncover a pro-inflammatory property of IL-30 that supports encephalitogenic immunity in vivo.

Pulmonary insults exacerbate susceptibility to oral Listeria monocytogenes infection through the production of IL-10 by NK cells

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host’s ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including Natural Killer (NK) cells. Lastly, the ability of Ncr1+ derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.

The synergistic effects of elevated temperature and CO2-induced ocean acidification reduce cardiac performance and increase disease susceptibility in subadult, female American lobsters Homarus americanus H. Milne Edwards, 1837 (Decapoda: Astacidea: Nephropidae) from the Gulf of Maine

Increased greenhouse gas emissions have caused rapid ocean warming (OW) and reduced ocean pH via acidification (OA). Both OW and OA will likely impact marine crustaceans, but they are often examined in isolation. We conducted an environmental-stressor experiment to understand how exposure to current summer conditions (16 °C, pH 8.0), OW only (20 °C, pH 8.0), OA only (16 °C, pH 7.6), or both acidification and warming, OAW (20 °C, pH 7.6), differentially influence thermal physiology and immune response of female subadults of the American lobster, Homarus americanus H. Milne Edwards, 1837. Following a 42 d exposure, cardiac performance was assessed during an acute thermal stress, and lobsters were subjected to a subsequent 21 d pathogen challenge with the bacterium Aerococcus viridans var. homari, the causative agent of gaffkemia. Lobsters under OAW had significantly lower (P ≤ 0.02) Arrhenius break temperatures (ABT), an indicator of thermal limits of capacity, compared to lobsters exposed to all other treatments, suggesting these stressors act synergistically to reduce physiological performance. Individuals from the OW and OAW treatments also had significantly lower (P ≤ 0.035) total hemocyte counts (THCs), an indicator of immune response, and showed a reduced median time to death (by up to 5 d sooner) post A. viridans injection compared to lobsters exposed to current summer conditions. Moreover, nearly twice as many lobsters exposed to OAW lost at least one claw during the pathogen challenge compared to all other treatment groups, potentially increasing the risk of mortality due to secondary infection. Together, these results suggest that OAW will impact the physiology and immune response of subadult H. americanus, potentially influencing successful recruitment to the fishery.

Transgenerational Self-Reconstruction of Disrupted Chromatin Organization After Exposure To An Environmental Stressor in Mice

Exposure to environmental stressors is known to increase disease susceptibility in unexposed descendants in the absence of detectable genetic mutations. The mechanisms mediating environmentally-induced transgenerational disease susceptibility are poorly understood. We showed that great-great-grandsons of female mice exposed to tributyltin (TBT) throughout pregnancy and lactation were predisposed to obesity due to altered chromatin organization that subsequently biased DNA methylation and gene expression. Here we analyzed DNA methylomes and transcriptomes from tissues of animals ancestrally exposed to TBT spanning generations, sexes, ontogeny, and cell differentiation state. We found that TBT elicited concerted alterations in the expression of “chromatin organization” genes and inferred that TBT-disrupted chromatin organization might be able to self-reconstruct transgenerationally. We also found that the location of “chromatin organization” and “metabolic” genes is biased similarly in mouse and human genomes, suggesting that exposure to environmental stressors in different species could elicit similar phenotypic effects via self-reconstruction of disrupted chromatin organization.

Polymorphisms of F2, PROC, PROZ, and F13A1 Genes are Associated With Recurrent Spontaneous Abortion in Chinese Han Women

Mutations of hemostasis/coagulation-related genes have been speculated to cause recurrent spontaneous abortion (RSA). This study investigated the genetic association between the polymorphisms of factor V (F5), factor II (F2), antithrombin (SERPINC1), protein C (PROC), protein S (PROS1), protein Z (PROZ), factor XIII (F13A1), and carboxypeptidase B2 (CPB2) genes and RSA. The 426 patients with RSA and 444 controls were recruited in this study, and single-nucleotide polymorphisms (SNPs) were analyzed by using SNPscan technology. Genotype and allele frequencies of rs3136520 in F2, rs3024731 in PROZ, and rs1050782 in F13A1 showed statistically significant differences between the 2 groups. TT genotype of rs3136520 ( P = .031, odds ratio [OR] = 0.986, 95% confidence interval [CI] = 0.976-0.997) and AA genotype of rs2069906 in PROC ( P = .021, OR = 0.114, 95% CI = 0.014-0.902) in their recessive models and AG + GG variants of rs1050782 ( P = .007, OR = 0.681, 95% CI = 0.516-0.899) in the dominant model might be associated with the reduced risk of RSA. AT + TT variants of rs3024731 ( P = .010, OR = 1.479, 95% CI = 1.098-1.994) may increase disease susceptibility in dominant model. Haplotype analysis of rs3024731 and rs3024735 in PROZ displayed that the AA and TG haplotype were inclined to decrease and increase the risk of RSA, respectively. These results suggested that rs3136520, rs2069906, rs3024731, and rs1050782 may have a significant association with the genetic susceptibility of RSA in Chinese Han women.

Telomere dynamics may link stress exposure and ageing across generations

Although exposure to stressors is known to increase disease susceptibility and accelerate ageing, evidence is accumulating that these effects can span more than one generation. Stressors experienced by parents have been reported to negatively influence the longevity of their offspring and even grand offspring. The mechanisms underlying these long-term, cross-generational effects are still poorly understood, but we argue here that telomere dynamics are likely to play an important role. In this review, we begin by surveying the current connections between stress and telomere dynamics. We then lay out the evidence that exposure to stressors in the parental generation influences telomere dynamics in offspring and potentially subsequent generations. We focus on evidence in mammalian and avian studies and highlight several promising areas where our understanding is incomplete and future investigations are critically needed. Understanding the mechanisms that link stress exposure across generations requires interdisciplinary studies and is essential to both the biomedical community seeking to understand how early adversity impacts health span and evolutionary ecologists interested in how changing environmental conditions are likely to influence age-structured population dynamics.

Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus

Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell–derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.