Focal adhesion dynamics in cellular function and disease.

Today, adoptive cell therapy has many successes in cancer therapy, and this subject is brilliant in using chimeric antigen receptor T cells. The CAR T cell therapy, with its FDA-approved drugs, could treat several types of hematological malignancies and thus be very attractive for treating solid cancer. Unfortunately, the CAR T cell cannot be very functional in solid cancers due to its unique features. This treatment method has several harmful adverse effects that limit their applications, so novel treatments must use new cells like NK cells, NKT cells, and macrophage cells. Among these cells, the CAR macrophage cells, due to their brilliant innate features, are more attractive for solid tumor therapy and seem to be a better candidate for the prior treatment methods. The CAR macrophage cells have vital roles in the tumor microenvironment and, with their direct effect, can eliminate tumor cells efficiently. In addition, the CAR macrophage cells, due to being a part of the innate immune system, attended the tumor sites. With the high infiltration, their therapy modulations are more effective. This review investigates the last achievements in CAR-macrophage cells and the future of this immunotherapy treatment method. 

The CAR macrophage cells, a novel generation of chimeric antigen-based approach against solid tumors

Background Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Methods Immunohistochemistry, Western blotting, HE RhoAflox/flox (cKO) mice or Lyz2Cre+/- (Cre) mice, regardless of sex. Macrophages' migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages. Results 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Conclusions Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.

/pdf/macrophage-specific-rhoa-knockout-delays-wallerian-2x73y1oc1i.pdf

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively. 

Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response

Diagnosis of interstitial lung diseases (ILD) is difficult to perform. Extracellular vesicles (EVs) facilitate cell-to-cell communication, and they are released by a variety of cells. Our goal aimed to investigate EV markers in bronchoalveolar lavage (BAL) from idiopathic pulmonary fibrosis (IPF), sarcoidosis and hypersensitivity pneumonitis (HP) cohorts. ILD patients followed at Siena, Barcelona and Foggia University Hospitals were enrolled. BAL supernatants were used to isolate the EVs. They were characterized by flow cytometry assay through MACSPlex Exsome KIT. The majority of alveolar EV markers were related to the fibrotic damage. CD56, CD105, CD142, CD31 and CD49e were exclusively expressed by alveolar samples from IPF patients, while HP showed only CD86 and CD24. Some EV markers were common between HP and sarcoidosis (CD11c, CD1c, CD209, CD4, CD40, CD44, CD8). Principal component analysis distinguished the three groups based on EV markers with total variance of 60.08%. This study has demonstrated the validity of the flow cytometric method to phenotype and characterize EV surface markers in BAL samples. The two granulomatous diseases, sarcoidosis and HP, cohorts shared alveolar EV markers not revealed in IPF patients. Our findings demonstrated the viability of the alveolar compartment allowing identification of lung-specific markers for IPF and HP.

/pdf/the-effects-of-interstitial-lung-diseases-on-alveolar-3k49gv2z.pdf

The Effects of Interstitial Lung Diseases on Alveolar Extracellular Vesicles Profile: A Multicenter Study

Cysteinyl-leukotrienes (cys-LTs) have well-characterized physiopathological roles in the development of inflammatory diseases. We have previously found that protein tyrosine phosphatase e (PTPe) is a signaling partner of CysLT1R, a high affinity receptor for leukotriene D4 (LTD4). There are two major isoforms of PTPe, receptor-like (RPTPe) and cytoplasmic (cyt-)PTPe, both of which are encoded by the PTPRE gene but from different promoters. In most cells, their expression is mutually exclusive, except in human primary monocytes, which express both isoforms. Here, we show differential PTPe isoform expression patterns between monocytes, M1 and M2 human monocyte-derived macrophages (hMDMs), with the expression of glycosylated forms of RPTPe predominantly in M2-polarized hMDMs. Using PTPe-specific siRNAs and expression of RPTPe and cyt-PTPe, we found that RPTPe is involved in monocyte adhesion and migration of M2-polarized hMDMs in response to LTD4 Altered organization of podosomes and higher phosphorylation of the inhibitory Y-722 residue of ROCK2 was also found in PTPe-siRNA-transfected cells. In conclusion, we show that differentiation and polarization of monocytes into M2-polarized hMDMs modulates the expression of PTPe isoforms and RPTPe is involved in podosome distribution, ROCK2 activation and migration in response to LTD4.

RPTPε promotes M2-polarized macrophage migration through ROCK2 signaling and podosome formation.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease characterized by antigen-triggered neutrophilic exacerbations. Although CD4+ T cells are sufficient for HP pathogenesis, this never translated into efficient T cell-specific therapies. Increasing evidence shows that B cells also play decisive roles in HP. Here, we aimed to further define the respective contributions of B and T cells in subacute experimental HP.Mice were subjected to a protocol of subacute exposure to the archaeon Methanosphaera stadmanae to induce experimental HP. Using models of adoptive transfers of B cells and T cells in Rag1-deficient mice and of B cell-specific S1P1 deletion, we assessed the importance of B cells in the development of HP by evaluating inflammation in bronchoalveolar lavage fluid. We also aimed to determine if injected antibodies targeting B and/or T cells could alleviate HP exacerbations using a therapeutic course of intervention.Even though B cells are not sufficient to induce HP, they strongly potentiate CD4+ T cell-induced HP‑associated neutrophilic inflammation in the airways. However, the reduction of 85% of lung B cells in mice with a CD19-driven S1P1 deletion does not dampen HP inflammation, suggesting that lung B cells are not necessary in large numbers to sustain local inflammation. Finally, we found that injecting antibodies targeting B cells after experimental HP was induced does not dampen neutrophilic exacerbation. Yet, injection of antibodies directed against B cells and T cells yielded a potent 76% inhibition of neutrophilic accumulation in the lungs. This inhibition occurred despite partial, sometimes mild, depletion of B cells and T cells subsets.Although B cells are required for maximal inflammation in subacute experimental HP, partial reduction of B cells fails to reduce HP-associated inflammation by itself. However, co-modulation of T cells and B cells yields enhanced inhibition of HP exacerbation caused by an antigenic rechallenge. 

/pdf/co-modulation-of-t-cells-and-b-cells-enhances-the-inhibition-1p4iznyh.pdf

Co-modulation of T cells and B cells enhances the inhibition of inflammation in experimental hypersensitivity pneumonitis

Lung cancer is the leading cause of cancer-related deaths. While the recent use of immune checkpoint inhibitors significantly improves patient outcomes, responsiveness remains restricted to a small proportion of patients. Conventional dendritic cells (DCs) play a major role in anticancer immunity. In mice, two subpopulations of DCs are found in the lung: DC2s (CD11b+Sirpα+) and DC1s (CD103+XCR1+), the latest specializing in the promotion of anticancer immune responses. However, the impact of lung cancer on DC populations and the consequent influence on the anticancer immune response remain poorly understood. To address this, DC populations were studied in murine models of Lewis Lung Carcinoma (LLC) and melanoma-induced lung metastasis (B16F10). We report that direct exposure to live or dead cancer cells impacts the capacity of DCs to differentiate into CD103+ DC1s, leading to profound alterations in CD103+ DC1 proportions in the lung. In addition, we observed the accumulation of CD103loCD11b+ DCs, which express DC2 markers IRF4 and Sirpα, high levels of T-cell inhibitory molecules PD-L1/2 and the regulatory molecule CD200. Finally, DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to the anti-PD-1 immune checkpoint therapy; the co-injection restored sensitivity to immunotherapy. Thus, we demonstrate that lung tumor development leads to the accumulation of CD103loCD11b+ DCs with a regulatory potential combined with a reduced proportion of highly-specialized antitumor CD103+ DC1s, which could promote cancer growth. Additionally, promoting an anticancer DC signature could be an interesting therapeutic avenue to increase the efficacy of existing immune checkpoint inhibitors.

Countering the advert effects of lung cancer on the anticancer potential of dendritic cell populations reinstates sensitivity to anti-PD-1 therapy

ZNF768 loss amplifies p53 action and reduces lung tumorigenesis in mice

Generation and characterization of a Cre-inducible ZNF768 overexpression mouse model

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