Bacterial infections, particularly Salmonella, pose a significant health risk to neonates due to their underdeveloped immune systems. Understanding the immune responses in the neonatal intestine during S. Typhimurium infection is crucial for developing effective therapeutic and prevention strategies. This study found neonatal rats exhibited severe symptoms, including significant mortality, body weight loss, diarrhea, and bacterial load increases in the gastrointestinal tract and various organs, particularly in the ileum. Moreover, neonatal rats exhibited a high percentage of type 3 immune cells including Th17, γδT17, and ILC3 after S. Typhimurium infection. Furthermore, cintirorgon treatment during early life, the agonist of RORγt, significantly enhanced IL-17A-secreting type 3 immune response and alleviated the symptoms. Our data reveal targeting RORγt and IL-17A pathways may offer a promising therapeutic strategy for bacterial infections in neonatal populations.

Diabetic kidney disease (DKD) is the leading cause of chronic renal pathology. Understanding the molecular underpinnings of DKD is critical to designing tailored therapeutic approaches. Here, we focused on sex differences and the contribution of aging toward the progression of DKD. To explore these questions, we utilized young (12 weeks old) and aged (approximately 50 weeks old) type 2 diabetic nephropathy (T2DN) rats. We revealed that the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway was upregulated in T2DN rats compared with nondiabetic Wistar rats and in type 2 diabetic human kidneys. The activation of the cGAS/STING signaling pathway exhibited distinct protein expression profiles between male and female T2DN rats, with these differences becoming more pronounced with aging. RNA-Seq analysis of the kidney cortex in both male and female T2DN rats, at both younger and older ages, revealed several key molecules, highlighting crucial genes within the cGAS/STING pathway. Thus, our study delved deep into understanding the intricate sexual differences in the development and progression of DKD and we propose the cGAS/STING pathway as an essential contributor to disease development.

Background: Sepsis is characterized as a critical condition involving life-threatening organ dysfunction stemming from an imbalanced host immune response to infections. Survivors of sepsis face an increased risk of post-hospital discharge mortality along with potential long-term cognitive and functional impairments. Recent research has uncovered the roles of innate lymphoid cells (ILCs) in the borders of the central nervous system (CNS), extending beyond their well-established functions in immune regulation and neuroinflammation. ILCs may play a pivotal role in the pathophysiology of sepsis, influencing immunity, inflammation, and brain barrier homeostasis. Here we investigated the role of subtypes ILC1, ILC2, and ILC3 on experimental sepsis-induced cognitive decline. Methods Adult male Wistar rats were submitted to sepsis by cecal ligation and perforation (CLP) surgery or sham (non-CLP) surgery as the control group. Ten days after sepsis induction, all the rats were submitted to a novel object recognition (NOR) task, a non-spatial, declarative memory known as recognition memory and were euthanized. The presence of ILCs was evaluated in the choroid plexus (CP), meninges, brain, spleen, and gut using multi-channel flow cytometry. Results We observed that Wistar rats recovered from sepsis showed deficits in recognition memory, with no discernible difference in the count of ILCs between the CLP and non-CLP groups. However, we found a significant difference between ILC subtypes in the meninges and CP in the CLP group. Conclusions This finding further reinforces the notion that sepsis survivors commonly experience cognitive deficits post-recovery. Additionally, it implies that the involvement of specific ILCs subtypes may be significant during the acute phase of sepsis pathophysiology, but their impact diminishes after the recovery period.

Infiltrating T cells in the kidney amplify salt-sensitive (SS) hypertension and renal damage, but the mechanisms are not known. Genetic deletion of T cells (SSCD247-/-) or of the p67phox subunit of NADPH oxidase 2 (NOX2; SSp67phox-/-) attenuates SS hypertension in the Dahl SS rat. We hypothesized that reactive oxygen species produced by NOX2 in T cells drive the SS phenotype and renal damage. T cells were reconstituted by adoptively transferring splenocytes (∼10 million) from the Dahl SS (SS→CD247) rat, the SSp67phox-/- rat (p67phox→CD247), or only PBS (PBS→CD247) into the SSCD247-/- rat on postnatal day 5. Animals were instrumented with radiotelemeters and studied at 8 wk of age. There were no detectable differences in mean arterial pressure (MAP) or albuminuria between groups when rats were maintained on a low-salt (0.4% NaCl) diet. After 21 days of high-salt diet (4.0% NaCl), MAP and albuminuria were significantly greater in SS→CD247 rats compared with p67phox→CD247 and PBS→CD247 rats. Interestingly, there was no difference between p67phox→CD247 and PBS→CD247 rats in albuminuria or MAP after 21 days. The lack of CD3+ cells in PBS→CD247 rats and the presence of CD3+ cells in rats that received the T cell transfer demonstrated the effectiveness of the adoptive transfer. No differences in the number of CD3+, CD4+, or CD8+ cells were observed in the kidneys of SS→CD247 and p67phox→CD247 rats. These results indicate that reactive oxygen species produced by NOX2 in T cells participates in the amplification of SS hypertension and renal damage.NEW & NOTEWORTHY Our current work used the adoptive transfer of T cells that lack functional NADPH oxidase 2 into a genetically T cell-deficient Dahl salt-sensitive (SS) rat model. The results demonstrated that reactive oxygen species produced by NADPH oxidase 2 in T cells participate in the amplification of SS hypertension and associated renal damage and identifies a potential mechanism that exacerbates the salt-sensitive phenotype.

Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells. To gather insights into the function of these neural IgGs, CRISPR-Cas9 of IgG2B constant heavy chain encoding gene (Igh6), IgG2B overexpression, proximal labeling of rat astrocytes IgG2B and targets identification through 2D gels were performed. In Igh6 KO astrocytes, overrepresentation of factors involved in hematopoietic cells, neural stem cells, and the regulation of neuritogenesis have been identified. Moreover, overexpression of IgG2B in astrocytes induces the CRTC1-CREB-BDNF signaling pathway known to be involved in gliogenesis, whereas Igh6 KO triggers the BMP/YAP1/TEAD3 pathway activated in astrocytes dedifferentiation into neural progenitors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1. These experiments also suggest that proximal IgG2B-LAT1 interaction occurs concomitantly with MACO-1 and C2CD2L, at the heart of a potentially novel cell signaling platform. Finally, we demonstrated that these chains are synthesized individually and associated to recognize specific targets. Indeed, intermediate filaments Eif4a2 and Pdia6 involved in astrocyte fate constitute targets for these neural IgGs. Taken together, we hypothese that neural aberrant IgG chains may act as gatekeepers of astrocytes' fate.
© 2023. The Author(s).