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RAB11FIP5-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.

ABSTRACT: Rab11 recycling endosomes are involved in immunological synaptic functions, but the roles of Rab11 family-interacting protein 5 (Rab11Fip5), one of the Rab11 effectors, in the immune system remain obscure. Our previous study demonstrated that RAB11FIP5 transcripts are significantly elevated in PBMCs from HIV-1-infected individuals, making broadly HIV-1-neutralizing Abs compared with those without broadly neutralizing Abs; however, the role of Rab11FiP5 in immune functions remains unclear. In this study, a RAB11FIP5 gene knockout (RAB11FIP5 ^-/-) mouse model was employed to study the role of Rab11Fip5 in immune responses. RAB11FIP5 ^-/- mice exhibited no perturbation in lymphoid tissue cell subsets, and Rab11Fip5 was not required for serum Ab induction following HIV-1 envelope immunization, Ab transcytosis to mucosal sites, or survival after influenza challenge. However, differences were observed in multiple transcripts, including cytokine genes, in lymphocyte subsets from envelope-immunized RAB11FIP5 ^-/- versus control mice. These included alterations in several genes in NK cells that mirrored observations in NKs from HIV-infected humans expressing less RAB11FIP5, although Rab11Fip5 was dispensable for NK cell cytolytic activity. Notably, immunized RAB11FIP5 ^-/- mice had lower IL4 expression in CD4⁺ T follicular helper cells and showed lower TNF expression in CD8⁺ T cells. Likewise, TNF-α production by human CD8⁺ T cells correlated with PBMC RAB11FIP5 expression. These observations in RAB11FIP5 ^-/- mice suggest a role for Rab11Fip5 in regulating cytokine responses.

SUBMITTER: Li D

PROVIDER: S-EPMC8050958 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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<i>RAB11FIP5</i>-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.

Li Dapeng D Bradley Todd T Cain Derek W DW Pedroza-Pacheco Isabela I Aggelakopoulou Maria M Parks Robert R Barr Maggie M Xia Shi-Mao SM Scearce Richard R Bowman Cindy C Stevens Grace G Newman Amanda A Hora Bhavna B Chen Yue Y Riebe Kristina K Wang Yunfei Y Sempowski Gregory G Saunders Kevin O KO Borrow Persephone P Haynes Barton F BF

ImmunoHorizons 20201110 11

Rab11 recycling endosomes are involved in immunological synaptic functions, but the roles of Rab11 family-interacting protein 5 (Rab11Fip5), one of the Rab11 effectors, in the immune system remain obscure. Our previous study demonstrated that <i>RAB11FIP5</i> transcripts are significantly elevated in PBMCs from HIV-1-infected individuals, making broadly HIV-1-neutralizing Abs compared with those without broadly neutralizing Abs; however, the role of Rab11FiP5 in immune functions remains unclear. ...[more]

PMID: 33172842

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Project description:Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

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RAB11FIP5-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.

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<i>RAB11FIP5</i>-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.

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RAB11FIP5-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.

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&lt;i&gt;RAB11FIP5&lt;/i&gt;-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.

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OmicsDI is part of the ELIXIR infrastructure

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<i>RAB11FIP5</i>-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures.