Regulación de la activación de macrófagos alveolares por la proteína del surfactante pulmonar SP-A

Para facilitar el intercambio gaseoso, el pulmón tiene la mayor área del cuerpo en contacto con el medio externo. Se estima que hay alrededor de 300 millones de alvéolos en pulmones humanos adultos, lo que supone un área de contacto con el exterior 60 veces mayor que la superficie de la piel. Esta extensa superficie de contacto con el medio externo facilita la oxigenación, pero aumenta el riesgo de infección e inflamación por patógenos y endotoxinas presentes en el aire que respiramos. De hecho, el epitelio respiratorio es, con frecuencia, la puerta de entrada de microorganismos y alérgenos causantes de numerosas enfermedades. El sistema inmune innato en los alvéolos se caracteriza por una respuesta inmune humoral (lactoferrina, lisozima, colectinas pulmonares (SP-A y SP-D), β- defensinas y otros péptidos antimicrobianos) y celular, constituida principalmente por los macrófagos alveolares que coordinan la defensa del huésped [1]. Los macrófagos alveolares promueven la tolerancia a antígenos inocuos presentes en el aire inhalado, reduciendo la respuesta inflamatoria que podría comprometer la integridad de pulmón [1, 2]. Sin embargo, durante una infección, los macrófagos reconocen señales de alarma a través de receptores capaces de inducir programas de activación especializados. La activación clásica de los macrófagos (M1) es inducida por IFN-γ y patrones moleculares asociados a patógenos que son ligandos de TLR [1, 2]. Sin embargo, los macrófagos también adquieren un programa de activación alternativa (M2) en respuesta a IL-4 e IL-13, importante para la respuesta inmune ante infecciones parasitarias y para la reparación del tejido [3-6]..

Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of type 2-mediated macrophage activation. In the lung, surfactant protein A (SP-A) enhanced interleukin-4 (IL-4)-dependent macrophage proliferation and activation, accelerating parasite clearance and reducing pulmonary injury after infection with a lung-migrating helminth. In the peritoneal cavity and liver, C1q enhancement of type 2 macrophage activation was required for liver repair after bacterial infection, but resulted in fibrosis after peritoneal dialysis. IL-4 drives production of these structurally related defense collagens, SP-A and C1q, and the expression of their receptor, myosin 18A. These findings reveal the existence within different tissues of an amplification system needed for local type 2 responses

Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH

Spatial distribution and evaluation of risk factors for bovine neosporosis in Rondônia, Brazil

ABSTRACT Neospora caninum is an important worldwide parasite responsible for causing abortion in animals. Due to limited information on the occurrence of infection by this parasite in the state of Rondônia, Brazil, this study aimed to determine the seroprevalence and identify the risk factors associated with the infection in slaughtered cattle, from 19 municipalities distributed in seven microregions of the state. A total of 494 samples were obtained and subjected to anti-N. caninum antibodies, using the Indirect Immunofluorescence Reaction technique. Antibodies were detected in 5.06% (25/494) of the samples, in 30.30% (10/33) of farms, in nine municipalities located in four microregions of Rondônia. Of all the animals analyzed, 4.81% of the females (20/416) and 6.41% of the males (05/78) were seropositive for the parasite, with “abortion in the last 12 months” being considered an important risk factor for the occurrence of infection (OR = 9.54; p = 0.01). The present study points out the prevalence of anti-N. caninum antibodies in 5.06% of slaughtered animals and abortion as the main risk factor associated with infection by N. caninum, thus contributing to the elucidation of the epidemiology of this protozoan in Rondônia, Brazil

A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation

The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation

Tissue-specific contribution of macrophages to wound healing

AbstractMacrophages are present in all tissues, either as resident cells or monocyte-derived cells that infiltrate into tissues. The tissue site largely determines the phenotype of tissue-resident cells, which help to maintain tissue homeostasis and act as sentinels of injury. Both tissue resident and recruited macrophages make a substantial contribution to wound healing following injury. In this review, we evaluate how macrophages in two fundamentally distinct tissues, i.e. the lung and the skin, differentially contribute to the process of wound healing. We highlight the commonalities of macrophage functions during repair and contrast them with distinct, tissue-specific functions that macrophages fulfill during the different stages of wound healing

Comment and Response to “Do Client Characteristics Really Drive the Big N Audit Quality Effect? New Evidence from Propensity Score Matching” by Mark DeFond, David H. Erkens, and Jieying Zhang

This discussion presents the comments by the authors of Lawrence et al. [Lawrence A, Minutti-Meza M, Zhang P (2011) Can Big 4 versus non-Big 4 differences in audit-quality proxies be attributed to client characteristics? Accounting Rev. 86(1):259–286] to the critique of their study in DeFond et al. [DeFond M, Erkens DH, Zhang Z (2017) Do client characteristics really drive the Big N audit quality effect? New evidence from propensity score matching. Management Sci. 63(11):3628–3649] and response by the authors of the latter study