Hyaluronan is made and extruded from cells to form a pericellular or extracellular matrix (ECM) and is present in virtually all tissues in the body. The size and form of hyaluronan present in tissues are indicative of a healthy or inflamed tissue, and the interactions of hyaluronan with immune cells can influence their response. Thus, in order to understand how inflammation is regulated, it is necessary to understand these interactions and their consequences. Although there is a large turnover of hyaluronan in our bodies, the large molecular mass form of hyaluronan predominates in healthy tissues. Upon tissue damage and/or infection, the ECM and hyaluronan are broken down and an inflammatory response ensues. As inflammation is resolved, the ECM is restored, and high molecular mass hyaluronan predominates again. Immune cells encounter hyaluronan in the tissues and lymphoid organs and respond differently to high and low molecular mass forms. Immune cells differ in their ability to bind hyaluronan and this can vary with the cell type and their activation state. For example, peritoneal macrophages do not bind soluble hyaluronan but can be induced to bind after exposure to inflammatory stimuli. Likewise, naïve T cells, which typically express low levels of the hyaluronan receptor, CD44, do not bind hyaluronan until they undergo antigen-stimulated T cell proliferation and upregulate CD44. Despite substantial knowledge of where and when immune cells bind hyaluronan, why immune cells bind hyaluronan remains a major outstanding question. Here, we review what is currently known about the interactions of hyaluronan with immune cells in both healthy and inflamed tissues and discuss how hyaluronan binding by immune cells influences the inflammatory response.

Hyaluronan is a hygroscopic glycosaminoglycan that contributes to both extracellular and pericellular matrices. While the production of hyaluronan is essential for mammalian development, less is known about its interaction and function with immune cells. Here we review what is known about hyaluronan in the lung and how it impacts immune cells, both at homeostasis and during lung inflammation and fibrosis. In the healthy lung, alveolar macrophages provide the first line of defense and play important roles in immunosurveillance and lipid surfactant homeostasis. Alveolar macrophages are surrounded by a coat of hyaluronan that is bound by CD44, a major hyaluronan receptor on immune cells, and this interaction contributes to their survival and the maintenance of normal alveolar macrophage numbers. Alveolar macrophages are conditioned by the alveolar environment to be immunosuppressive, and can phagocytose particulates without alerting an immune response. However, during acute lung infection or injury, an inflammatory immune response is triggered. Hyaluronan levels in the lung are rapidly increased and peak with maximum leukocyte infiltration, suggesting a role for hyaluronan in facilitating leukocyte access to the injury site. Hyaluronan can also be bound by hyaladherins (hyaluronan binding proteins), which create a provisional matrix to facilitate tissue repair. During the subsequent remodeling process hyaluronan concentrations decline and levels return to baseline as homeostasis is restored. In chronic lung diseases, the inflammatory and/or repair phases persist, leading to sustained high levels of hyaluronan, accumulation of associated immune cells and an inability to resolve the inflammatory response.

Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44 −/− mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44 −/− AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44 −/− AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44 −/− mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44 −/− AMs. Oxidized phospholipids were more cytotoxic to CD44 −/− AMs and induced greater lung inflammation in CD44 −/− mice. Reconstitution of CD44 +/+ mice with CD44 −/− bone marrow as well as adoptive transfer of CD44 −/− AMs into CD44 +/+ mice showed that lipid accumulation in CD44 −/− AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44 −/− mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44 −/− AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44 −/− AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.

The process of autophagy is conserved among all eukaryotes from yeast to humans and is mainly responsible for bulk degradation of cellular contents and nutrient recycling during starvation. Autophagy has been suggested to play a role in the pathogenesis of the opportunistic human fungal pathogen , potentially through a contribution to the export of virulence factors. In this study, we showed that deletion of each of the, ,, and genes in leads to autophagy-related phenotypes, including impaired amino acid homeostasis under nitrogen starvation. In addition, the Δ mutants were hypersensitive to inhibition of the ubiquitin-proteasome system, a finding consistent with a role in amino acid homeostasis. Although eachΔ mutant was not markedly impaired in virulence factor production , we found that all four genes contribute to virulence in a murine inhalation model of cryptococcosis. Interestingly, these mutants displayed significant differences in their ability to promote disease development. A more detailed investigation of virulence for theΔ and Δ mutants revealed that both strains stimulated an exaggerated host immune response, which, in turn, contributed to disease severity. Overall, our results suggest that different genes are involved in nonautophagic functions and contribute to virulence beyond their core functions in autophagy.

Background: Early onset colorectal cancer (EoCRC), diagnosed in those <50 years old, is increasing in incidence. We sought to differentiate characteristics and outcomes of EoCRC in patients with sporadic disease or preexisting conditions. Methods: We evaluated 2,135 patients with EoCRC in a population-based cohort from the Canadian province of British Columbia. Patients were identified on the basis of presence of hereditary syndromes (n = 146) or inflammatory bowel disease (IBD; n = 87) and compared with patients with sporadic EoCRC (n = 1,902). Results: Proportions of patients with preexisting conditions were highest in the youngest decile of 18–29 (34.3%, P < 0.0001). Patients with sporadic EoCRC were older, more likely female, and had increased BMI (P < 0.05). IBD-related EoCRC had the highest rates of metastatic disease, poor differentiation, adverse histology, lymphovascular, and perineural invasion (P < 0.05). Survival was lower in patients with IBD (HR, 1.80; 95% CI, 1.54–3.13; P < 0.0001) and higher in hereditary EoCRC (HR, 0.47; 95% CI, 0.45–0.73; P < 0.0001) compared with sporadic. Prognosis did not differ between ulcerative colitis or Crohn's disease but was lower in those with undifferentiated-IBD (HR, 1.87; 95% CI, 1.01–4.05; P = 0.049). Lynch syndrome EoCRC had improved survival over familial adenomatous polyposis (HR, 0.31; 95% CI, 0.054–0.57; P = 0.0037) and other syndromes (HR, 0.43; 95% CI, 0.11–0.99; P = 0.049). In multivariate analysis controlling for prognostic factors, hereditary EoCRC was unchanged from sporadic; however, IBD-related EoCRC had worse overall survival (HR, 2.21; 95% CI, 1.55–3.16; P < 0.0001). Conclusions: EoCRC is heterogenous and patients with preexisting conditions have different characteristics and outcomes compared with sporadic disease. Impact: Prognostic differences identified here for young patients with colorectal cancer and predisposing conditions may help facilitate treatment planning and patient counseling. See related commentary by Hayes, p. 1775