A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance.

Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.

Targeting COPD with PLGA-Based Nanoparticles: Current Status and Prospects.

Chronic obstructive pulmonary disease (COPD) is pulmonary emphysema characterized by blockage in the airflow resulting in the long-term breathing problem, hence a major cause of mortality worldwide. Excessive generation of free radicals and the development of chronic inflammation are the major two episodes underlying the pathogenesis of COPD. Currently used drugs targeting these episodes including anti-inflammatory, antioxidants, and corticosteroids are unsafe, require high doses, and pose serious side effects. Nanomaterial-conjugated drugs have shown promising therapeutic potential against different respiratory diseases as they are required in small quantities which lower overall treatment costs and can be effectively targeted to diseased tissue microenvironment hence having minimal side effects. Poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) are safe as their breakdown products are easily metabolized in the body. Drugs loaded on the PLGA NPs have been shown to be promising agents as anticancer, antimicrobial, antioxidants, and anti-inflammatory. Surface modification of PLGA NPs can further improve their mechanical properties, drug loading potential, and pharmacological activities. In the present review, we have presented a brief insight into the pathophysiological mechanism underlying COPD and highlighted the role, potential, and current status of PLGA NPs loaded with drugs in the therapy of COPD.

Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice.

We evaluated the role of the thymus in development of multi-organ autoimmunity in human immune system (HIS) mice. T cells were essential for disease development and the same T cell clones with varying phenotypes infiltrated multiple tissues. De novo-generated hematopoietic stem cell (HSC)-derived T cells were the major disease drivers, though thymocytes pre-existing in grafted human thymi contributed if not first depleted. HIS mice with a native mouse thymus developed disease earlier than thymectomized mice with a thymocyte-depleted human thymus graft. Defective structure in the native mouse thymus was associated with impaired negative selection of thymocytes expressing a transgenic TCR recognizing a self-antigen. Disease developed without direct recognition of antigens on recipient mouse MHC. While human thymus grafts had normal structure and negative selection, failure to tolerize human T cells recognizing mouse antigens presented on HLA molecules may explain eventual disease development. These new insights have implications for human autoimmunity and suggest methods of avoiding autoimmunity in next-generation HIS mice.

Crossreactive public TCR sequences undergo positive selection in the human thymic repertoire.

We investigated human T-cell repertoire formation using high throughput TCRß CDR3 sequencing in immunodeficient mice receiving human hematopoietic stem cells (HSCs) and human thymus grafts. Replicate humanized mice generated diverse and highly divergent repertoires. Repertoire narrowing and increased CDR3ß sharing was observed during thymocyte selection. While hydrophobicity analysis implicated self-peptides in positive selection of the overall repertoire, positive selection favored shorter shared sequences that had reduced hydrophobicity at positions 6 and 7 of CDR3ßs, suggesting weaker interactions with self-peptides than unshared sequences, possibly allowing escape from negative selection. Sharing was similar between autologous and allogeneic thymi and occurred between different cell subsets. Shared sequences were enriched for allo-crossreactive CDR3ßs and for Type 1 diabetes-associated autoreactive CDR3ßs. Single-cell TCR-sequencing showed increased sharing of CDR3αs compared to CDR3ßs between mice. Our data collectively implicate preferential positive selection for shared human CDR3ßs that are highly cross-reactive. While previous studies suggested a role for recombination bias in producing "public" sequences in mice, our study is the first to demonstrate a role for thymic selection. Our results implicate positive selection for promiscuous TCRß sequences that likely evade negative selection, due to their low affinity for self-ligands, in the abundance of "public" human TCRß sequences.

Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival.

MyD88 signaling directly promotes T-cell survival and is required for optimal T-cell responses to pathogens. To examine the role of T-cell-intrinsic MyD88 signals in transplantation, we studied mice with targeted T-cell-specific MyD88 deletion. Contrary to expectations, we found that these mice were relatively resistant to prolongation of graft survival with anti-CD154 plus rapamycin in a class II-mismatched system. To specifically examine the role of MyD88 in Tregs, we created a Treg-specific MyD88-deficient mouse. Transplant studies in these animals replicated the findings observed with a global T-cell MyD88 knockout. Surprisingly, given the role of MyD88 in conventional T-cell survival, we found no defect in the survival of MyD88-deficient Tregs in vitro or in the transplant recipients and also observed intact cell homing and expression of Treg effector molecules. MyD88-deficient Tregs also fail to protect allogeneic bone marrow transplant recipients from chronic graft-versus-host disease, confirming the observations of defective regulation seen in a solid organ transplant system. Together, our data define MyD88 as having a divergent requirement for cell survival in non-Tregs and Tregs, and a yet-to-be defined survival-independent requirement for Treg function during the response to alloantigen.

Giant cavernous haemangioma of the wandering spleen.

Cavernous haemangioma is a rare disorder of the spleen with fewer than 100 cases reported [1]. Spleen may have an unusual degree of mobility and occupy an atypical location in less than 0.2 % of all the patients [2] Wandering spleen has been associated with incomplete fusion or even absence of gastrosplenic and lienorenal ligaments [3]. A 36-year-old woman presented with a six-month history of pain in the left hypochondrium and a massive splenomegaly. Ultrasonography, Doppler studies, and computed tomography were performed. Ultrasonography showed a large heterogeneous solid cystic mass, measuring 11.2 cm × 10.6 cm, located in the pelvis. Thin soft tissue connecting this mass to spleen noticed. Spleen was malrotated & in left lumbar fossa. Doppler studies shows prominent vessels at the periphery of the mass with high velocity external flow and scanty vascularity at the centre, probably suggesting haemangioma. Contrast-enhanced computed tomography (CECT) of the abdomen showed spleen in left lumbar region with a large heterogeneous, predominantly cystic mass lesion measuring 11.2 x 10.6 cm seen arising from diaphragmatic surface of lower pole of the spleen (Fig. 1), findings were suggestive of wandering spleen with a haemangioma or a hydatid cyst. The patient was explored by a left para-median incision under general anaesthesia. Peroperatively, there was a malrotated enlarged spleen with a large solid lesion confined to the lower half of the spleen (Fig. 2). Gastrosplenic ligament was not visualized. Total splenectomy was done after ligating the splenic artery as the main splenic artery was supplying the mass.