Mucosal Homeostasis In The Healthy Lung Flashcards
Pneumonia video
explained (not really focus of lecture)
Homeostasis in the alveolar space
Differentiation of challenges without bystander damage in a tissue that is fragile!
lungs in constant contact w/ harmless or pathogenic elements
e.g. grass, dust mites, spores cats, food
Tissue Histology:
Type 1 and 2 AEC
equilibrium b/w normal gas exchange and inflammation
Immune cell interactions in the healthy lung
The lung has specialised
tissue-resident immune cells
* Dendritic cells
* Alveolar macrophages
* Regulatory T cells
Meet the alveolar macrophage (7+1 marks)
- CD11c ++ SiglecF+ F4/80 int
- Resident phagocytic patrolling cells
- Pro and anti inflammatory
- Remove apoptotic cells by efferocytosis
- Induce regulatory T cells via retinoic acid
- Mixed functional phenotype – highly phagocytic
and capable of producing TNF-⍺ and IL-1 but also
responsive to IL-4 and able to drive type 2 inflammation
as well as potentially wound healing – a response that is site specific - Important sentinels in asthma – depletion exacerbates disease
Alveolar macrophage ontogeny and turnover
diagram
Macrophage activation is a balancing act
no need to memorise receptors fully!!!!
* Activation of alveolar macrophages
depends on a balance between signals
leading to activation and inhibition
* In the absence of inflammation
regulation predominates through
negative signals
* The epithelia raises the threshold above
which macrophages get activated
* Negative signals are provided by the
airway epithelium and soluble
molecules like mucus
* Regulation is linked to macrophage
function i.e. clearance of apoptotic cells
Homeostasis in the alveolar space
in situ negative regulation
- Regulation is highly
dependent on contact
with epithelia, setting a
threshold above witch
macrophages activate - Antigen plus a disruption
of the epithelia drives
macrophage activity - After inflammation the
tissue adapts to a novel
state of regulation – we
are never the same after
inflammation
Control of innate immunity in the airway
images
Regulation of alveolar macrophages in the absence of antigenic stimulation
images
Alveolar macrophage shape the composition of the lung mucosal microbiome
CD200 – CD200R signals regulate macrophage activity and change the bacterial species present in the airway
image
Infections alter the state of regulation in homeostasis by affecting macrophage function
The expression of CD200R by
macrophages increases as
Influenza infection proceeds
=
Leading to susceptibility to bacterial
pneumonia
Inflammatory responses in asthma
video
How do we study immune mechanisms behind susceptibility to
bacterial pneumonia during asthma?
HDM allergen exposure in mice
recapitulates a pathology that is
comparable to human Asthma
S.pneumoniae induces lethal pneumonia in asthmatic mice due to neutropenia
look at: Bacterial recovery
from tissues and Blunted neutrophil
recruitment
What is different in alveolar macrophages in different states of altered health?
Apoptotic cells are present in most inflammatory conditions and their clearance is required
Apoptotic cell clearance regulates alveolar macrophages
TAM receptors control cytokine production and TLR signalling
altering macrophage function
Apoptotic cell clearance is
a hallmark of resolution in
inflammation
The role of sugars and the mucus
Siglec-F Sialic acid binding
immunoglobulin-type lectin
Siglec-F is expressed by alveolar
macrophages extracted by lavage
Macrophages interact with mucins both in “health” and in inflammation via Siglecs
Siglec-F signals decrease the expression of Trem2 and Axl on alveolar macrophages
Key points
- Chronic conditions like asthma are not only or necessarily exacerbated by infection
- Individuals with chronic respiratory conditions (or after acute inflammation) have an altered state of health that affects their response to infections
- This altered state of health might be associated with a different level of regulation or activity of immune cells (alveolar macrophages) in the lungs
- Alveolar macrophages interact with the environment in different ways in homeostasis or after inflammation
- All of these principles seem to apply to multiple inflammatory conditions
- The integrity and activity of the epithelia is key to maintain homeostasis
Altered macrophage regulation after inflammation
Alveolar macrophages are long-lived but do not return to the same state of regulation after inflammation
Immune properties of epithelial cells (many cells)
images
The diverse epithelial component and their interactions with resident and recruited immune cells
image
Summary
- The lung mucosal epithelia is not just a barrier, it interacts with
commensals and immune cells to maintain homeostasis and initiate
regulated immune responses - The lung epithelia express a group of receptors that provide signals that
control and harness macrophage function - Soluble factors also regulate macrophage function (environment)
- The integrity of the epithelia is essential to maintain mucosal immune homeostasis
- High expression of negative regulators, and negative feedback loops by TAM receptors, are predominant in resolution tipping the balance of macrophage function towards regulation
- Alveolar macrophages change their responsiveness with every
inflammatory response and phenotypic changes might be prolonged suggesting a process of adaptation - These data highlight the importance of understanding the mechanisms of mucosal regulation in health and the differed states of “altered health”
Some key interactions between resident/recruited cells of the lung
diagram
